Transdermal therapeutic systems (TTS) as pharmaceutical administration forms have been known for a long time. For the transdermal administration of active pharmaceutical ingredients by means of TTS, the stratum corneum (SC), the outermost layer of the skin, in the majority of cases constitutes the real barrier for the permeability and for the rate of passage of the active pharmaceutical ingredient.
Peptides and proteins and also other high-molecular molecules, with a molecular weight of more than 500 daltons—such as, for example, tacrolimus, heparin, and numerous salts of betamethasone—are generally not absorbed transdermally, owing to their molecular size and to their physicochemical properties.
Moreover, the majority of peptides possess a low oral bioavailability and are subject to severe, proteolytic degradation in the gastrointestinal tract. For these reasons, peptides are commonly administered parenterally, bypassing the gastrointestinal tract. This involves injections or infusions which are administered below the skin, into the muscle or directly into the bloodstream.
The transdermal route here would offer a noninvasive alternative—with high patient compliance—to this invasive, parenteral administration. Consequently there are numerous approaches to facilitating the permeability of the skin for molecules having a molecular weight of more than 500 daltons. These approaches include, primarily, the use of permeation enhancers or the additional use of heat.
Another technique for making molecules with poor skin transit amenable to transdermal administration is to facilitate the passage of an active ingredient of this kind through the stratum corneum by partly destroying or removing this layer beforehand. These techniques, referred to as “skin ablation”, use thermal or mechanical energy in order to effect partial destruction or removal of the stratum corneum and hence to create direct channels into the living epidermis. The permeability of the skin is increased and the transdermal absorption of high-molecular-weight molecules can therefore be made possible.
As a result of this pretreatment of the skin, moreover, it is also possible for hydrophilic active ingredients to be administered transdermally, the transdermal route having hitherto been closed to such ingredients on account of their hydrophilicity. Ingredients contemplated here include, for example, fentanyl citrate, granisetrone HCl, Na diclofenac, and apomorphine sulfate. Furthermore, the TTS area of existing TTS systems can be reduced significantly, for the same blood levels, by means of skin ablation pretreatment.
The skin ablation technique commonly generates a multiplicity of microchannels through the stratum corneum, and yet the percentage “perforated” proportion of the treated skin area is relatively small. A description of the laser skin ablation technique is present in WO 2007/039646, whose equivalent is United States Patent Publication No. 2008/255034 A1.
Follicle-stimulating hormone (FSH, follitropin) is a gonadotropic hormone of the anterior lobe of the hypophysis, and is also called follicle maturation hormone, gonadotropin A, prolan A or thylakentrin. Human FSH is an acidic glycoprotein (isoelectric point 4.5) with a 16% carbohydrate fraction and a molecular weight of around 34 000 daltons. Its α-polypeptide chain (with 92 amino acid residues) is virtually identical with that of chorio(nic)gonadotrop(h)in. The β-chain, which is specific for FSH, contains 111 amino acid residues. FSH promotes growth and development of the gonads and incites them to hormone synthesis. In women, it plays a part in the menstrual cycle, by causing a new follicle to mature and to produce estradiol. In the human gonads, it stimulates the formation of spermatogenic cells. For the use described here, it is possible to use FSH from natural sources or recombinant FSH.
FSH has a relatively short half-life. In the context of the superovulation of ruminants, hypophyseal extracts have been much used, and then, however, may contain not only FSH but also varying amounts of LH (luteinizing hormone). Today, recombinant FSH products are also available commercially (GONAL F®, PUREGON®).
Somatropin (also: somatotropic hormone, STH, GH) is a species-specific hormone which is formed in the anterior lobe of the hypophysis and is responsible for the growth process. The human growth hormone, also called HGH (hypophyseal or human growth hormone), is an individual polypeptide, with a molar mass of about 21 500, composed of 191 amino acids with 2 disulfide bridges. In terms of its composition, human somatotropin is closely related to placental lactogen and also to prolactin. In liver and kidney, somatotropin causes the excretion of insulinlike growth factors which are responsible for much of the effects of somatropin. Somatotropin secretion is inhibited by somatostatin, and stimulated by the releasing hormone somatoliberin (SRF or SRH or GH-RF or GH-RH) from the hypothalamus.
Dwarfism caused in children by the absence or under-production of somatotropin can be regulated by supply of human growth hormone, which has since been produced recombinantly in the USA as PROTROPIN® (Genentech) and—with a different amino acid residue—HUMATROPE® (Eli Lilly). Other medical applications for somatotropin might arise in the case of burns, signs of aging, osteoporosis, cardiovascular disorders, and obesity.
The known products, however, possess certain disadvantages, which are attributable in particular to the low stability of the peptides in solution, this low stability being common knowledge.
Molecules of high molecular weight have to date been closed off from transdermal administration as a result of their physicochemical properties. Transdermal administration of these molecules is made possible only by pretreatment of the skin.
Lastly, injection itself may be accompanied by difficulties, which lie primarily in pain during application, a risk of injury, and the risk of infections.